Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis

Abstract

Background: Analyses of microRNA expression profiles have shown that many microRNAs are expressed aberrantly and correlate with tumorigenesis, progression, and prognosis of various haematological and solid tumours. We aimed to assess the relation between microRNA expression and progression and prognosis of gastric cancer.

Methods: 353 gastric samples from two independent subsets of patients from Japan were analysed by microRNA microarray. MicroRNA expression patterns were compared between non-tumour mucosa and cancer samples, graded by diffuse and intestinal histological types and by progression-related factors (eg, depth of invasion, metastasis, and stage). Disease outcome was calculated by multivariable regression analysis to establish whether microRNAs are independent prognostic factors.

Findings: In 160 paired samples of non-tumour mucosa and cancer, 22 microRNAs were upregulated and 13 were downregulated in gastric cancer; 292 (83%) samples were distinguished correctly by this signature. The two histological subtypes of gastric cancer showed different microRNA signatures: eight microRNAs were upregulated in diffuse-type and four in intestinal-type cancer. In the progression-related signature, miR-125b, miR-199a, and miR-100 were the most important microRNAs involved. Low expression of let-7g (hazard ratio 2.6 [95% CI 1.3-4.9]) and miR-433 (2.1 [1.1-3.9]) and high expression of miR-214 (2.4 [1.2-4.5]) were associated with unfavourable outcome in overall survival independent of clinical covariates, including depth of invasion, lymph-node metastasis, and stage.

Interpretation: MicroRNAs are expressed differentially in gastric cancers, and histological subtypes are characterised by specific microRNA signatures. Unique microRNAs are associated with progression and prognosis of gastric cancer.

Funding: National Cancer Institute.

Figure 1. MicroRNAs associated with progression of gastric cancer

(A) Venn diagram of microRNAs related to T (depth of invasion), N (lymph-node metastasis), and stage. Listed microRNAs comprise the progression signature. Numerals indicate the number of microRNAs. Molecules corresponding to every part of the Venn diagram are shown. MicroRNAs in H and M (haematogenous metastasis) and P and CY (peritoneal dissemination) that are similar to those for T, N, or stage are shown in red. (B) Mean expression levels of miR-125b, miR-199a, and miR-100 on microRNA array according to progression in disease stage. Mean expression levels are shown as linear-scale data on microRNA array analysed with GenePix Pro 6.0; the calculation is based on the intensity (brightness) of each pixel on the microarray image. Mean expression levels of non-tumour mucosa (Normal) of group 1 are also shown. miR-125b-1 and miR-125b-2 are located on different chromosomes but the sequence of mature microRNA is the same; miR-199a-1 and miR-199a-2 are also the same. For miR-100, two probes were included on the microRNA array.

Figure 2. Kaplan-Meier curves of independent prognostic factors for overall survival

Curves are depicted with data for 101 patients. MicroRNA expression levels measured on the microarray were converted into discrete variables by division of samples into two classes (high and low expression), with the respective mean levels of microRNA expression as a threshold. Censored cases are shown on the curves. p values are log rank.